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Cancer genetics
Original article
One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene
  1. Florentia Fostira1,
  2. Irene Kostantopoulou1,
  3. Paraskevi Apostolou1,
  4. Myrto S Papamentzelopoulou1,
  5. Christos Papadimitriou2,
  6. Eleni Faliakou3,
  7. Christos Christodoulou4,
  8. Ioannis Boukovinas5,
  9. Evangelia Razis6,
  10. Dimitrios Tryfonopoulos7,
  11. Vasileios Barbounis8,
  12. Andromache Vagena1,
  13. Ioannis S Vlachos9,
  14. Despoina Kalfakakou1,
  15. George Fountzilas10,
  16. Drakoulis Yannoukakos1
  1. 1 InRaSTES, Molecular Diagnostics Laboratory, National Centre for Scientific Research NCSR Demokritos, Athens, Greece
  2. 2 Second Department of Surgery, Oncology Unit, National and Kapodistrian University of Athens, Aretaiio Hospital, Athens, Greece
  3. 3 Breast Cancer Unit, Mitera Maternity Hospital, Athens, Greece
  4. 4 Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece
  5. 5 Department of Medical Oncology, Bioclinic of Thessaloniki, Thessaloniki, Greece
  6. 6 Third Department of Medical Oncology, Hygeia Hospital, Athens, Greece
  7. 7 Second Department of Medical Oncology, ‘Agios Savvas’ Anticancer Hospital, Athens, Greece
  8. 8 Third Medical Oncology Department, Metropolitan Hospital Athens, Athens, Greece
  9. 9 Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA
  10. 10 Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
  1. Correspondence to Dr Florentia Fostira, Molecular Diagnostics Laboratory, National Centre for Scientific Research NCSR Demokritos, Athens 15310, Greece; florentia_fostira{at}hotmail.com

Abstract

Background Gene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations.

Methods To further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case–control analysis.

Results Herein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively.

Conclusion Studying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

  • hereditary breast cancer
  • BRCA1
  • BRCA2
  • PALB2
  • NGS
  • gene panel
  • genetic testing

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jmedgenet-2019-106189

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    Footnotes

    • Contributors FF wrote the manuscript. FF and IK conceived and designed the work and interpreted the data. IK made essential contributions to the manuscript. PA, MSP and AV were involved in the laboratory analyses, collected family pedigrees and corrected the manuscript. CP, EF, CC, IB, ER, DT, VB were involved in patient collection, acquired patient data and corrected the manuscript. ISV and DK were involved in the bioinformatic analyses and interpretation of the results and corrected the manuscript. GF designed multiple aspects of the study and made essential contributions to the manuscript. DY conceived and supervised the study and made essential contributions to the manuscript. All authors provided critical feedback and approved the final version of the manuscript.

    • Funding This research was co-financed by the European Union (European Social Fund, ESF) and Greek national funds through the Operational Program ‘Education and Lifelong Learning’ of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology (ARISTEIA 39, P. BROCA), which invests in knowledge society through the ESF.

    • Competing interests None declared.

    • Patient consent for publication Obtained.

    • Ethics approval The study was approved by the Bioethics committee of NCSR ‘Demokritos’ (BCNCSRD-240/EHΔ/11.3, updated on 29 June 2015).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available in a public, open access repository. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.